Abstract
BACKGROUND: Emerging literature suggests that classic psychedelics may have efficacy in treating mood and substance use disorders in humans. This has raised questions regarding the primary therapeutic mechanism of these compounds. Here, we hypothesize that the reversal of and resilience against learned helplessness may be an important driver of the therapeutic mechanisms of classic psychedelics. Furthermore, we argue that the learned helplessness paradigm can provide a robust model to investigate the behavioral and mechanistic effects of classic psychedelics in both clinical and preclinical experiments. OPINION: We highlight the learned helplessness model and its potential utility in the psychedelic sphere for several reasons. First, learned helplessness is a robust phenomenon observed across multiple mammalian species including humans, and has been well described in terms of its neurobiology, behavioral effects, and clinical implications; current efforts in psychedelic research and theories of psychedelic mechanisms have yet to achieve this level of integration. Interestingly, there is substantial overlap in the neural circuits governing resilience against learned helplessness and psychedelic actions-such as those involving the dorsal raphe nucleus. Furthermore, our hypothesis that classic psychedelics can reverse helplessness behavior fits with much of the current preclinical data, which has shown that psychedelics improve performance in behavioral despair tasks in rodents. Here we make the case for bringing attention to these congruencies in an effort to advance toward mechanistic, behavioral, and transdiagnostic insights into the therapeutic effects of classic psychedelics, with the potential for learned helplessness to help explain some positive effects across levels of analysis.